Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen

Abstract

We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35-to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications.Tamoxifen (TAM) is the most widely used hormone therapy for breast cancer. Toremifene (TOR), a chlorinated derivative of TAM, is also an approved treatment for metastatic breast cancer in postmenopausal women.1,2 Although TAM is the prototypical drug in the selective estrogen receptor modulator (SERM) class, its clinical efficacy and safety are known to vary widely among individuals.3 TOR is equally effective in breast cancer treatment.4-7 However, TOR may have reduced genotoxicity and lower potential to induce secondary endometrial cancers 8,9 and may therefore be considered as an alternative to TAM as firstline therapy for patients with ER-positive advanced breast cancer.TAM is extensively metabolized. The clinical benefit of TAM is thought to arise from its conversion to active metabolites, chiefly 4-hydroxy TAM (4-OH TAM) and 4-OH-N-desmethyl TAM (4-OH-NDM TAM, otherwise known as endoxifen; Fig. 1). [10][11][12] These metabolites bind to the ER with up to 30-fold greater affinity than TAM, and this increased potency for binding translates into enhanced antiestrogen activity. 13-16Whether these metabolites are responsible for TAM's variable clinical efficacy is a topic of considerable controversy. TAM is known to be metabolized extensively by the cytochrome P450 (CYP) enzyme system, primarily by the CYP3A4 and 2D6 isoforms. 17 CYP3A4 generates the major circulating metabolite mono-NDM TAM 18; however, the formation of the active TAM metabolites apparently requires cytochrome P-450 2D6 (CYP2D6).19 CY...

Toremifene, rather than tamoxifen, might be a better option for the adjuvant endocrine therapy in CYP2D6*10T/T genotype breast cancer patients in China

“…For example, endoxifen appeared to contribute approximately 32% to the pharmacologic activity of TAM in the breast; however, 4-OH-NDM TOR did not contribute to the pharmacologic activity of TOR at all. These results suggested that differences in CYP2D6 activity were more likely to affect the clinical efficacy of TAM compared with TOR 25 . This study provides a reasonable explanation for our results.…”

“…Due to the chlorine atom on the side chain, TOR has a pharmacokinetic profile and metabolic pathway that differ from that of TAM, which may provide a therapeutic advantage in certain patients. The potential contribution of CYP2D6 in the bioactivation pathway of TOR may be lower compared to TAM . However, less is known about the relationship between CYP2D6 polymorphisms and the clinical efficacy of TOR .…”

“…The potential contribution of CYP2D6 in the bioactivation pathway of TOR may be lower compared to TAM. 25,26 However, less is known about the relationship between CYP2D6 polymorphisms and the clinical efficacy of TOR. 27 We performed a study to determine whether TOR could be an acceptable alternative for patients with genetic polymorphisms that reduce their ability to metabolize TAM in adjuvant endocrine treatment in China.…”

Do We Need Another Selective Estrogen Receptor Modulator for the Adjuvant Treatment of Breast Cancer?

“…Tamoxifen is converted to its active metabolites by the CYP2D6 gene, and because some selective serotonin uptake inhibitors are potent inhibitors of CYP2D6 activity, their concurrent use may substantially compromise the efficacy of tamoxifen 9,10 . In contrast, toremifene is primarily metabolized by CYP3A4, and CYP2D6 is thought to play a minor role 11 .…”

Evaluation of herb–drug interactions of Hovenia dulcis fruit extracts

“…[5] CYP enzymes are the major enzymes in the liver, which is a crucial organ for the drug metabolism of many conventional medicines. [67] Many herbs could affect the enzyme activity of CYP, which may cause alterations in the metabolic clearance of the substrate drug by inhibiting or inducing a specific CYP enzyme; these modifications may lead to decreased therapeutic effects or increased toxicity of certain drugs. [891011] For these reasons, assessments of herb–drug interactions involving CYP inhibition based on in vitro data should be executed, in order to prevent adverse effects caused by taking prescription medicines in combination with herbal products.…”